A synthetic peptide mimic kills Candida albicans and synergistically prevents infection

Sebastian Schaefer, Raghav Vij, Jakob L. Sprague, Sophie Austermeier, Hue Dinh, Peter R. Judzewitsch, Sven Müller-Loennies, Taynara Lopes Silva, Eric Seemann, Britta Qualmann, Christian Hertweck, Kirstin Scherlach, Thomas Gutsmann, Amy K. Cain, Nathaniel Corrigan, Mark S. Gresnigt, Cyrille Boyer (), Megan D. Lenardon () and Sascha Brunke ()
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Sebastian Schaefer: University of New South Wales (UNSW)
Raghav Vij: Hans Knoell Institute
Jakob L. Sprague: Hans Knoell Institute
Sophie Austermeier: Hans Knoell Institute
Hue Dinh: Macquarie University
Peter R. Judzewitsch: University of New South Wales (UNSW)
Sven Müller-Loennies: Leibniz Lung Center
Taynara Lopes Silva: Hans Knoell Institute
Eric Seemann: Jena University Hospital – Friedrich Schiller University Jena
Britta Qualmann: Jena University Hospital – Friedrich Schiller University Jena
Christian Hertweck: Hans Knoell Institute
Kirstin Scherlach: Hans Knoell Institute
Thomas Gutsmann: Leibniz Lung Center
Amy K. Cain: Macquarie University
Nathaniel Corrigan: University of New South Wales (UNSW)
Mark S. Gresnigt: Friedrich Schiller University Jena
Cyrille Boyer: University of New South Wales (UNSW)
Megan D. Lenardon: UNSW
Sascha Brunke: Hans Knoell Institute

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract More than two million people worldwide are affected by life-threatening, invasive fungal infections annually. Candida species are the most common cause of nosocomial, invasive fungal infections and are associated with mortality rates above 40%. Despite the increasing incidence of drug-resistance, the development of novel antifungal formulations has been limited. Here we investigate the antifungal mode of action and therapeutic potential of positively charged, synthetic peptide mimics to combat Candida albicans infections. Our data indicates that these synthetic polymers cause endoplasmic reticulum stress and affect protein glycosylation, a mode of action distinct from currently approved antifungal drugs. The most promising polymer composition damaged the mannan layer of the cell wall, with additional membrane-disrupting activity. The synergistic combination of the polymer with caspofungin prevented infection of human epithelial cells in vitro, improved fungal clearance by human macrophages, and significantly increased host survival in a Galleria mellonella model of systemic candidiasis. Additionally, prolonged exposure of C. albicans to the synergistic combination of polymer and caspofungin did not lead to the evolution of tolerant strains in vitro. Together, this work highlights the enormous potential of these synthetic peptide mimics to be used as novel antifungal formulations as well as adjunctive antifungal therapy.

Date: 2024
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DOI: 10.1038/s41467-024-50491-x

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